The selective chlorination of less than all the hydroxyl groups of a polyhydric alcohol can be a major synthesis problem, which can be made more complicated if the hydroxyl groups are of differing reactivity. The high intensity sweetener sucralose, a compound whose formal name is 4-chloro-4-deoxy-.alpha.-D-galactopyranosyl-1,6dichloro-1,6-dideoxy-.beta. -D-fructofuranoside, is a partially chlorinated derivative of sucrose having chlorine substituted for the hydroxyl groups in the 6', 4, and 1' positions. It is a major synthesis problem to direct the chlorination of sucrose only to the desired 6', 4, and 1' positions to produce sucralose. The initial process disclosed in the literature for the synthesis of sucralose involved the full selective protection of all the hydroxyl groups on the sucrose as follows:
(1) tritylation of sucrose at the 6, 1', and 6' primary hydroxyl groups with trityl chloride in pyridine; PA1 (2) acetylation of the tri-tritylsucrose at the 5 secondary positions; PA1 (3) removal of the trityl groups to give 2,3,4,3', 4'pentaacetylsucrose; PA1 (4) migration of the acetyl group on the 4-position to the 6-position to afford 2,3,6,3', 4'-pentaacetyl-sucrose; PA1 (5) chlorination of the free hydroxyls to produce sucralose pentaacetate; and PA1 (6) deacetylation of the sucralose pentaacetate. PA1 (a) adding at least seven molar equivalents of an acid chloride to a reaction mixture comprising a tertiary amide, in the presence of a sucrose-6-ester dissolved in the said reaction mixture, to form initially a chloroformimium chloride salt which subsequently forms an O-alkylformiminium chloride adduct with the hydroxyl groups of the sucrose-6-ester; PA1 (b) subjecting the reaction mixture product of step (a) to an elevated temperature not higher than about 85.degree. C. for a period of time sufficient to produce a mixture of chlorinated sucrose-6-ester products consisting essentially of monochlorosucrose-6-ester (believed to comprise primarily of 4- and 6'-mono-chloro isomers), 4,6'-dichloro-sucrose-6-ester, and 1', 6'-dichloro- sucrose-6-ester; and PA1 (c) subjecting the reaction mixture product of step (b) to an elevated temperature not higher than about 125.degree. C. for a period of time sufficient to produce a chlorinated product consisting essentially of 1', 4,6'-trichlorogalacto- sucrose-6-ester. PA1 (d) Hydrolysis of the non-chlorinated O-alkylformiminium chloride complexed hydroxyl groups at positions 2,3,3',4' of the trichlorinated sucrose-6-ester with aqueous alkali under such conditions of temperature and pH control as to minimize any concomitant 6-ester saponification. The resulting hydrolysate is preferably stabilized by the addition of sufficient acid to attain an approximately neutral pH; and PA1 (e) Extraction of the desired 4,1',6'-trichlorooalacto sucrose-6-ester into an appropriate water-immiscible organic solvent followed by crystallization of the product from an organic solvent, an organic solvent mixture, or preferably from an organic solvent-water mixture, thereby directly obtaining substantially improved yields of high-purity sucralose-6-ester without resorting to chromatographic or derivatization techniques.
The above-described process is disclosed, for example, by P. H. Fairclough, L. Hough, and A. C. Richardson, Carbohydr. Res., 40, 285 (1975); L. Hough, S. P. Phadnis, R. Khan, and M. R. Jenner, British Patents Nos. 1,543,167 and 1,543,168 (1979).
Considerable work has been carried out to determine the relative reactivities of the sucrose hydroxyl groups to chlorination. See, for instance, L. Hough, S. P. Phadnis, and E. Tarelli, Carbohydr. Res., 44, 35 (1975). The results indicate that the reactivity is 6 and 6'&lt;4&lt;1'&lt;4'&lt;others. Thus a mild chlorination yields 6,6'-dichlorosucrose, a more vigorous chlorination gives the 4,6,6'-trichloro species (the 4-position is chlorinated with inversion of configuration, hence the product is 4,6,6'-trichloro-4,6,6'-trideoxyoalactosucrose), and increasingly vigorous chlorinations give successively 4,6,1',6'-tetrachloro-4,6,1', 6'-tetradeoxygalactosucrose and 4,6,1', 4', 6'-pentachloro- 4,6,1', 4', 6'-pentadeoxygalactosucrose. From a consideration of this data it can be seen that blocking the 6-position with a readily removable protecting group such as a benzoate or acetate ester group, followed by trichlorination and removal of the protecting group, could yield sucralose without the need for full protection of all the hydroxyl groups.
The chlorination of partially protected carbohydrates is especially difficult because side reactions, such as oxidation and elimination, have a great tendency to occur. [From reviews dealing with the chlorination of carbohydrates, consult J. E. G. Barnett, Adv. Carbohydr Chem., 22, 177 (1967); and W. A. Szarek, Adv. Carbohydr. Chem. Biochem., 28. 225 (1973).]The relatively severe conditions required to chlorinate the unreactive neopentyl-like 1'- position of sucrose can, and often does, result in a product consisting primarily of dark degradation products and tars. (For reviews which discuss the chlorination of sucrose and its derivatives, consult: R. A. Khan, Adv. Carbohydr. Chem. Biochem., 33, 225 (1976); and M. R. Jenner in "Developments in Food Carbohydrates-2", C. K. Lee, Ed., Applied Science, London, 1980, pp. 91-143.)
Typically, the chlorinated products resulting from the chlorination of sucrose or its derivatives are purified and isolated by chromatographic techniques or by derivitization to form highly crystalline solids (e.g., peracetylation).